Macrophage migration inhibitory factor (MIF) is the first cytokine activity described and a key regulatory mediator that is released upon activation of different cell types (Bloom, et al., 1966, Science 153:80-82; David, 1966, Proc Natl Acad Sci USA 56:72-77; Bernhagen, et al., 2003, Nature 365:756-759). MIF increases macrophage antimicrobial responses and it is expressed upstream of cytokines such as tumor necrosis factor (TNF)-α, IFN-γ, and IL-1β (Calandra, et al., 2003 Nat Rev Immunol 3:791-800). MIF activates immune cells by binding to CD74, leading to the recruitment of CD44 into a signaling complex, the stimulation of nonreceptor tyrosine kinases, and initiation of the ERK1/2 MAP kinase pathway (Shi, et al., 2006 Immunity 25:595-606; Leng, et al., 2003, J Exp Med 197:1467-1476). The chemokine receptors CXCR2 and CXCR4 also become activated by MIF via noncognate interactions that are reinforced in the presence of CD74 (Bernhagen, et al., 2007, Nat Med 13:587-596). Among mesenchymal cell types, MIF binding to cardiomyocyte CD74 stimulates the AMP-activated kinase (AMPK) cascade to mediate protection from ischemic injury (Miller, et al., 2008, Nature 451:578-582; Qi, et al., 2009, J Clin Invest 119: 3807-3816).
Although MIF receptor knockout mice (CD74−/−) phenocopy features MIF deficiency (Meyer-Siegler, et al., 2006, J Immunol 177:8730-8739; Topilski, et al., 2002, J Immunol 168:1610-1617), recent observations have led to the hypothesis that there may be a second ligand for CD74. MIF-deficient B cells, for example, are more sensitive to apoptosis than wild-type B cells, but the magnitude of this defect is twofold more pronounced in CD74-deficient cells (Gore, et al., 2008, J Biol Chem 283:2784-2792). Intravital microscopy studies also have shown a more pronounced effect of antagonism of CD74 than MIF in monocyte arrest (Bernhagen, et al., 2007, Nat Med 13:587-596). Anti-MIF antibodies, although highly effective in experimental studies, do not completely inhibit CD74-dependent cellular activation responses (Chagnon, et al., 2005, Circ Res 96:1095-1102).
D-dopachrome tautomerase (D-DT) (also known as MIF-2) and MIF show a conserved intron-exon structure and their coding regions are highly homologous. The genes for MIF and D-DT are in close apposition to each other and to two theta-class glutathione S-transferases, suggesting that these gene clusters arose by an ancestral duplication event. D-DT was named for its ability to tautomerize the nonnaturally occurring, D-stereoisomer of dopachrome, which is a catalytic property shared with MIF. This activity has been hypothesized to be a vestigial function that reflects MIF's ancestral origin in the invertebrate melanotic encapsulation response (Fingerle-Rowson, et al., 2009, Mol Cell Biol 29:1922-1932). A crystal structure of D-DT has verified its 3D similarity with MIF (Sugimoto, et al., 1999, Biochemistry 38:3268-3279). With the exception of recent studies indicating an interaction between the MIF and D-DT genes in the expression of proangiogenic factors and COX-2 in adenocarcinoma cell lines (Xin, et al., 2010, Mol Cancer Res 8:1601-1609; Coleman, et al., 2008, J Immunol 181:2330-2337), there have been no studies of the biologic functions of D-DT.
Despite the advances made in the art for detecting and treating inflammation associated with MIF signaling through CD74, there is a need in the art for the detection and treatment of inflammation associated with other molecules that signal through CD74. The present invention fulfills these needs.